The androgen receptor (AR), a member of the steroid receptor superfamily, is a ligand-dependent transcription factor that mediates androgen action in cells and has been linked to many disorders like, balding, benign prostatic hyperplasia and prostate cancer. The AR is composed of three major domains: an NH2-terminal transcriptional activation domain, a central DNA-binding domain, and a COOH-terminal ligand-binding domain (LBD). The AR is associated with cellular chaperones in its inactive state, however, after binding to androgens such as testosterone and dihydrotestosterone (DHT), the AR undergoes a conformation change and dissociates from its cellular chaperones. The AR forms homodimers and interacts with coactivators and chromatin modifying enzymes, and it also binds to androgen-response elements (ARE) within the genome. These ARE regulate expression of genes relevant to prostatic growth and function. Additionally, ARE have been linked to cancer development and progression. Among the numerous genes regulated by the AR, AR activation has been shown to upregulate expression of prostate specific antigen (PSA), cyclin-dependent kinases (cdk) 1, 2 and 4, cyclin A and B, keratinocytes growth factor, survivin, hypoxia-inducible factor-1a, and insulin-like growth factor-1 receptor (IGF-IR). Moreover, AR mutation, amplification, and/or overexpression often occur and are involved in the development of androgen-independent growth of prostate cancer.
Prostate cancer is the most common cancer and the second most common cause of cancer death among men in the United States. It is expected that 218,890 men will be diagnosed with and 27,050 men will die from this disease in 2007. As detection techniques improve, an increasing number of patients are diagnosed with localized disease, whereas the number of patients with disseminated diseases are on the decline. Metastasis, however, still occurs prior to the initial diagnosis in many patients, and hence eradication of primary tumors by either surgery or radiation therapy is not curative. Because prostate cancer is insensitive to most chemotherapeutic agents clinically available, hormonal manipulations are the mainstay treatment for advanced disease. Current hormonal therapies, however, are palliative and can only slow the progression of advanced prostate cancer by an average of less than 18 months. As such, there is an urgent need to develop more effective therapeutic modalities for both prostate cancer and for other disorders affected by androgen receptor activity.